ArticleJCI insight2019
ER stress and Rho kinase activation underlie the vasculopathy of CADASIL.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- Age-dependent vascular and neurological characteristics of CADASIL are recapitulated in Notch3 mutant zebrafish, implicating a role for type IV collagen in disease progression.Acta neuropathologica communications · 2026Article
- L-Type Voltage-Gated CaMedical sciences (Basel, Switzerland) · 2026Article
- 3D Vessels-on-Chip using isogenic hiPSC-derived VSMCs reveal NOTCH3-driven alterations in brain small vessel disease.Stem cell reports · 2026Article
- Selective vulnerability of cerebral vasculature toScience advances · 2026Article
- Simultaneous onset of visual dysfunction and cerebral infarction in a young patient with CADASIL: a case report.Frontiers in medicine · 2026Article
- Extracellular domain shedding of NOTCH3 during endocytosis associated with heterogeneity between different CADASIL mutant activation mechanisms.Cell communication and signaling : CCS · 2025Article
- Reactive oxygen species in hypertension.Nature reviews. Cardiology · 2025Review
- CADASIL: A NOTCH3-associated cerebral small vessel disease.Journal of advanced research · 2024Review
- Impact of arterial stiffness on cerebrovascular function: a review of evidence from humans and preclincal models.American journal of physiology. Heart and circulatory physiology · 2024Review
- Progress to Clarify HowBiomolecules · 2024Review
- ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics.Acta neuropathologica communications · 2023Article
- KRIT1: A Traffic Warden at the Busy Crossroads Between Redox Signaling and the Pathogenesis of Cerebral Cavernous Malformation Disease.Antioxidants & redox signaling · 2023Review
- Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.Journal of clinical neurology (Seoul, Korea) · 2023Review
- Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM).Antioxidants (Basel, Switzerland) · 2022Article
- Vascular dysfunction and increased cardiovascular risk in hypospadias.European heart journal · 2022Article
- Transcription Factor HEY1 Improves Brain Vascular Endothelial Cell Function and Alleviates Ischemic Stroke by Upregulating NOTCH3.Neurochemical research · 2022Article
- Notch signalling in healthy and diseased vasculature.Open biology · 2022Review
- Oxidative Stress and Hypertension.Circulation research · 2021Review
- Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment.Scientific reports · 2021Article
- Review
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) leads to premature stroke and vascular dementia. Mechanism-specific therapies for this aggressive cerebral small vessel disease are lacking. CADASIL is caused by NOTCH3 mutations that influence vascular smooth muscle cell (VSMC) function through unknown processes. We investigated molecular mechanisms underlying the vasculopathy in CADASIL focusing on endoplasmic reticulum (ER) stress and RhoA/Rho kinase (ROCK). Peripheral small arteries and VSMCs were isolated from gluteal biopsies of CADASIL patients and mesentery of TgNotch3R169C mice (CADASIL model). CADASIL vessels exhibited impaired vasorelaxation, blunted vasoconstriction, and hypertrophic remodeling. Expression of NOTCH3 and ER stress target genes was amplified and ER stress response, Rho kinase activity, superoxide production, and cytoskeleton-associated protein phosphorylation were increased in CADASIL, processes associated with Nox5 upregulation. Aberrant vascular responses and signaling in CADASIL were ameliorated by inhibitors of Notch3 (γ-secretase inhibitor), Nox5 (mellitin), ER stress (4-phenylbutyric acid), and ROCK (fasudil). Observations in human CADASIL were recapitulated in TgNotch3R169C mice. These findings indicate that vascular dysfunction in CADASIL involves ER stress/ROCK interplay driven by Notch3-induced Nox5 activation and that NOTCH3 mutation-associated vascular pathology, typical in cerebral vessels, also manifests peripherally. We define Notch3-Nox5/ER stress/ROCK signaling as a putative mechanism-specific target and suggest that peripheral artery responses may be an accessible biomarker in CADASIL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.